Vitamin functionalized gel-forming block copolymers for biomedical applications

Abstract

Gel-forming block copolymers were prepared comprising i) a central hydrophilic block consisting essentially of a divalent poly(ethylene oxide) chain and ii) two peripheral monocarbonate or polycarbonate hydrophobic blocks. The hydrophobic blocks comprise one or more vitamin-bearing subunits. The vitamin-bearing subunits comprise a carbonate backbone portion and a side chain comprising a covalently bound form of a vitamin. The gel-forming block copolymers can be used to prepare various biodegradable and/or biocompatible hydrogel and organogel drug compositions, in particular antimicrobial and/or anti-tumor drug compositions. The hydrogel compositions can be suitable for depot injections. Synergistic enhancement of toxicity to microbes was observed with compositions comprising an antimicrobial cationic polymer and an antimicrobial compound.

What is claimed is: 
     
       1. A gel-forming block copolymer having a structure in accordance with formula (1): 
       
         
           
           
               
               
           
         
       
       wherein
 d′ is a positive number having a value of about 100 to about 600, 
 each K′ is an independent divalent linking group selected from the group consisting of O, NH, S, and combinations thereof, 
 each P a  is an independent monocarbonate or polycarbonate chain comprising 1 to about 10 vitamin-bearing subunits, wherein each of the vitamin-bearing subunits comprises a carbonate backbone portion and a side chain linked to the carbonate backbone portion, the side chain comprising a covalently bound form of a vitamin, 
 Z a  is a first end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons, and 
 Z b  is a second end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons. 
 
     
     
       2. The gel-forming block copolymer of  claim 1 , wherein each K′ is O. 
     
     
       3. The gel-forming block copolymer of  claim 1 , wherein each K′ is NH. 
     
     
       4. The gel-forming block copolymer of  claim 1 , wherein each K′ is S. 
     
     
       5. The gel-forming block copolymer of  claim 1 , wherein each P a  consists essentially of 1 to about 8 vitamin-bearing subunits. 
     
     
       6. The gel-forming block copolymer of  claim 1 , wherein the vitamin is selected from the group consisting of vitamin E compounds, vitamin D compounds, and combinations thereof. 
     
     
       7. The gel-forming block copolymer of  claim 1 , wherein each of the vitamin-bearing subunits comprises an alpha-tocopheryl moiety. 
     
     
       8. The gel-forming block copolymer of  claim 1 , wherein each of the vitamin-bearing subunits comprises an ergocalcipheryl moiety. 
     
     
       9. The gel-forming block copolymer of  claim 1 , wherein Z a  is hydrogen and Z b  is hydrogen. 
     
     
       10. The gel-forming block copolymer of  claim 1 , wherein the vitamin-bearing subunits of the gel-forming block copolymer have the structure: 
       
         
           
           
               
               
           
         
       
     
     
       11. The gel-forming block copolymer of  claim 1 , wherein the vitamin-bearing subunits of the gel-forming block copolymer have the structure: 
       
         
           
           
               
               
           
         
       
     
     
       12. The gel-forming block copolymer of  claim 1 , wherein the gel-forming block copolymer has a structure according to formula (1-A): 
       
         
           
           
               
               
           
         
       
       wherein
 the carbonate backbone atoms are numbered 1 to 6 in each carbonate subunit, 
 d′ is a positive number having a value of about 100 to about 600, 
 each m′ is an independent positive number having a value of 2 to about 20, 
 each L d  is independently a single bond or a divalent linking group comprising 1 to about 15 carbons, 
 each V is an independent moiety comprising a covalently bound form of a vitamin, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl, 
 each R″ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, 
 each t is an independent positive integer having a value of 0 to 2, 
 each t′ is an independent positive integer having a value of 0 to 2, 
 no carbonate subunit has t=0 and t′=0, 
 Z a  is a first end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons, and 
 Z b  is a second end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons. 
 
     
     
       13. The gel-forming block copolymer of  claim 12 , wherein Z a  is hydrogen and Z b  is hydrogen. 
     
     
       14. The gel-forming block copolymer of  claim 12 , wherein each t is 1 and each t′ is 1. 
     
     
       15. The gel-forming block copolymer of  claim 12 , wherein each R′ is hydrogen. 
     
     
       16. The gel-forming block copolymer of  claim 12 , wherein each t is 1, each t′ is 1, and each R′ is hydrogen. 
     
     
       17. The gel-forming block copolymer of  claim 1 , wherein the gel-forming block copolymer has a structure according to formula (1-B): 
       
         
           
           
               
               
           
         
       
       wherein
 the carbonate backbone atoms are numbered 1 to 6 in each carbonate subunit, 
 d′ is a positive number having a value of about 100 to about 600, 
 each m′ is an independent positive number having a value of 2 to about 20, 
 each L e  is independently a single bond or a divalent linking group comprising 1 to about 15 carbons, 
 each V′ is an independent moiety comprising a covalently bound form of a vitamin, 
 each R′ is an independent monovalent radical selected from the group consisting of hydrogen, halogens, methyl, and ethyl, 
 each R″ is an independent monovalent radical selected from the group consisting of hydrogen and alkyl groups comprising 1 to 6 carbons, 
 Z a  is a first end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons, and 
 Z b  is a second end group selected from the group consisting of hydrogen and groups comprising 1 to about 15 carbons. 
 
     
     
       18. The gel-forming block copolymer of  claim 17 , wherein Z a  is hydrogen and Z b  is hydrogen. 
     
     
       19. The gel-forming block copolymer of  claim 17 , wherein R″ is methyl. 
     
     
       20. The gel-forming block copolymer of  claim 17 , wherein R″ is ethyl.